Skip to main content
NCBI home page
Cancer Science logoLink to Cancer Science
. 2023 Feb 8;114(5):1792–1799. doi: 10.1111/cas.15734

Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers

Yasuto Takeuchi 1,2, Noriko Gotoh 1,2,✉
PMCID: PMC10154879  PMID: 36704829

Abstract

As the incidence of breast cancer continues to increase, it is critical to develop prevention strategies for this disease. Inflammation underlies the onset of the disease, and NF‐κB is a master transcription factor for inflammation. Nuclear factor‐κB (NF‐κB) is activated in a variety of cell types, including normal epithelial cells, cancer cells, cancer‐associated fibroblasts (CAFs), and immune cells. Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer, and not all DCIS lesions develop into invasive breast cancers (IBC). Currently, most patients with DCIS undergo surgery with postoperative therapy, although there is a risk of overtreatment. In BRCA mutants, receptor activator of NF‐κB (RANK)‐positive progenitors serve as the cell of origin, and treatment using the RANK monoclonal antibody reduces the risk of IBC. There is still an unmet need to diagnose malignant DCIS, which has the potential to progress to IBC, and to establish appropriate prevention strategies. We recently demonstrated novel molecular mechanisms for NF‐κB activation in premalignant mammary tissues, which include DCIS, and the resultant cytokine‐enriched microenvironment is essential for breast cancer development. On the early endosomes in a few epithelial cells, the adaptor protein FRS2β, forming a complex with ErbB2, carries the IκB kinase (IKK) complex and leads to the activation of NF‐κB, thereby inducing a variety of cytokines. Therefore, the FRS2β‐NFκB axis in the inflammatory premalignant environment could be targetable to prevent IBC. Further analysis of the molecular mechanisms of inflammation in the premalignant microenvironment is necessary to prevent the risk of IBC.

Keywords: breast cancer, DCIS, FRS2, NF‐κB, premalignant microenvironment

Inflammation underlies the onset of breast cancer, and NF‐kappaB is a master transcription factor for inflammation. We recently demonstrated novel molecular mechanisms for NF‐kappaB activation in premalignant mammary tissues. An adaptor protein FRS2beta carries the IkappaB kinase (IKK) complex, leading to the activation of NF‐kappaB in mammary epithelial cells.

graphic file with name CAS-114-1792-g003.jpg

Abbreviations

AID

cytidine deaminase

CAFs

cancer‐associated fibroblasts

ctDNA

circulating tumor DNA

DCIS

Ductal carcinoma in situ

DCs

dendritic cells

EGFR

epidermal growth factor receptor

EMT

epithelial‐mesenchymal transition

IBC

invasive breast cancer

IGF

insulin growth factor

IKK

IκB kinase

IL

interleukin

MDSCs

myeloid‐derived suppressor cells

MMTV

mouse mammary tumor virus

NF‐κB

nuclear factor‐κB

NKs

natural killer cells

NSAIDs

non‐steroidal anti‐inflammatory drugs

PD1

programmed cell death protein 1

PI3K

phosphatidylinositol 3‐kinase

PTB

phosphotyrosine binding

PTGS

prostaglandin‐endoperoxide synthase

RANK

receptor activator of NF‐κB

ROS

reactive oxygen species

RTKs

receptor tyrosine kinases

SERMs

estrogen receptor modulator

TAMs

tumor‐associated macrophages

TGF

transforming growth factor

TNF

tumor necrosis factor

VEGF

vascular endothelial growth factor

1. INTRODUCTION

Despite recent advancements in basic and clinical research, the incidence of breast cancer has continued to increase. 1 Breast cancer is the most common malignancy in women worldwide. 2 One in 20 women worldwide and one in nine women in Japan develop breast cancer. 3 Both genetic and nongenetic factors influence the development of breast cancer. The most representative breast cancer susceptibility genes are BRCA1 and BRCA2, which were discovered in the mid‐1990s. 4 , 5 These genes are involved in the repair of double‐strand breaks caused by homologous recombination. They account for approximately 2.5% of all breast cancer cases and affect women with a family history of breast cancer.

In contrast, non‐genetic factors include aging, reproductive factors (e.g., age at menarche and menopause and childbearing), 6 , 7 , 8 , 9 obesity, 10 , 11 alcohol, 12 physical activity, 13 and bacterial infection. 14 , 15 Inflammation triggered by any of these factors is thought to underlie the development of breast cancer. Although the precise molecular mechanisms remain obscure, targeting inflammation is an important strategy to prevent the development of breast cancer and decrease its incidence. In this review, we provide an overview of the current understanding of how inflammation contributes to the onset of breast cancer and the available preventive treatment options. We also discuss novel diagnostic and preventive strategies.

2. THE INFLAMMATORY MASTER TRANSCRIPTION FACTOR NF‐κB IS A KEY REGULATOR OF CANCER DEVELOPMENT

The physiological inflammatory response of the immune system is a normal reaction in the healing process that terminates upon the completion of pathological states. 16 However, when the inflammatory response persists, inflammatory mediators, such as cytokines, prostaglandins, reactive oxygen species (ROS), and reactive nitrogen species, can induce genetic mutations that induce carcinogenesis. 17 The activation of NF‐κB, a master transcription factor for inflammatory responses, is involved in the release of these mediators. Activated NF‐κB promotes cell proliferation, apoptosis, migration, invasion, and angiogenesis during tumor development. 18 Genetic instability and epigenetic modifications are also induced by NF‐κB activation. 19 Another mechanism by which NF‐κB stimulates tumor initiation is induction of the mutator enzyme cytidine deaminase (AID). 20 NF‐κB activation in cancer cells confers cancer stem‐like traits, 21 , 22 epithelial‐mesenchymal transition (EMT), 23 and resistance to chemotherapy. 24 Furthermore, NF‐κB controls inflammatory responses in the tumor microenvironment, which supports tumor initiation and progression. 25

Non‐steroidal anti‐inflammatory drugs (NSAIDs), including aspirin, are considered promising candidates for cancer prevention therapies because they are less expensive and have relatively few side effects. Previous studies have demonstrated their effectiveness in preventing the development of cancer, especially colorectal cancer. 26 The long‐term use of aspirin has been reported to reduce the incidence and mortality of colorectal cancer by one‐third. 27 Clinical studies for other cancer types, including breast cancer, have shown modest effects of aspirin in suppressing the incidence or mortality of the disease. 28 , 29 The principal mechanism of its antitumor effect is the inhibition of prostaglandin‐endoperoxide synthase 1 (PTGS1; also known as COX1) and PTGS2 (COX2). 30 , 31 COX1 and COX2 promote prostaglandin synthesis from arachidonic acid and sustain inflammatory signals triggered by the NF‐κB pathway, leading to cell proliferation, angiogenesis, and resistance to apoptosis. 32 Furthermore, they induce activation of the Wnt–β‐catenin pathway, thereby promoting cancer development and growth. 33

The tumor microenvironment consists of a diverse variety of immune cells, including tumor‐associated macrophages (TAMs), T cells, dendritic cells (DCs), myeloid‐derived suppressor cells (MDSCs), and natural killer cells (NKs). 34 , 35 The activation of NF‐κB in these immune cells is upregulated by the tumor necrosis factor (TNF) and interleukin (IL)‐1, for example. 36 The induction of NF‐κB signaling in immune cells promotes the production of inflammatory cytokines and chemokines, such as TNF, IL‐1, IL‐6, and vascular endothelial growth factor (VEGF). 37 These immune cell‐derived inflammatory cytokines stimulate NF‐κB activation in cancer cells, while cancer cell‐derived inflammatory cytokines recruit more immune cells into the tumor microenvironment. For example, NF‐κB‐induced CCL2 in cancer cells induces the activation of T cells and macrophage infiltration. 38 Thus, activation of NF‐κB signaling in both cancer cells and immune cells establishes a feed‐forward loop that promotes tumor growth along with the inflammatory state.

Nuclear factor‐κB activation in macrophages and T cells leads to both pro‐tumorigenic and anti‐tumorigenic effects, suggesting that the function of the NF‐κB subunit is context‐dependent. There are two types of tumor‐associated macrophages (M1 and M2), and type polarization is reversible. 39 The activation of NF‐κB p55 subunit has been reported to regulate the polarity of macrophages toward M1. 40 M1 macrophages produce inflammatory cytokines, such as TNF, IL‐1, IL‐2, IL‐6, IL‐12, and IL‐23, through NF‐κB signaling, and function in a tumor‐suppressive manner. In contrast, M2 macrophages produce anti‐inflammatory mediators, such as IL‐10 and transforming growth factor (TGF)‐β, which have a pro‐tumorigenic role. 17 NF‐κB activation in T cells stimulates effector T cells and increases the number of IFNγ‐producing CD8+ T cells that exhibit a tumor‐suppressive role. 41 NF‐κB also promotes immunosuppressive functions of Tregs and serves in a tumor‐promoting fashion. 42 Signaling via VEGF and programmed cell death protein 1 (PD1), an immune checkpoint molecule, inactivates DC maturation and acts in a pro‐tumorigenic manner. 43 MDSCs promote IL‐6 production, inactivation of T cells, and recruitment of M2 macrophages and Tregs via IL‐1‐mediated NF‐κB activation, resulting in an immunosuppressive microenvironment. 44 In contrast, NF‐κB activation in natural killer (NK) cells induces the expression of perforin and granzyme B, thereby demonstrating their ability to kill cancer cells directly. 45

3. DUCTAL CARCINOMA IN SITU (DCIS) AND CURRENT THERAPIES AGAINST DUCTAL CARCINOMA IN SITU FOR PREVENTION OF INVASIVE DISEASES

Ductal carcinoma in situ is a pathogenesis observed in the earliest stages of breast cancer and accounts for 25% of newly diagnosed breast cancer cases. 46 , 47 DCIS is a lesion in which cancer cells localize within the mammary duct and do not invade the basement membrane. The diagnosis of DCIS often involves the detection of calcifications by mammography. 48 Biopsy is performed for definitive diagnosis when suspicious calcifications are observed on mammography. The pathological diagnosis classifies DCIS as low‐to high‐grade (grades 1–3) based on the morphological architecture and cytonuclear features. 49 The higher the grade, the higher the risk of invasive breast cancer (IBC), 50 , 51 although the prognostic estimation is not accurate. Recent basic research using lineage tracing, genomics, and transcriptomics has provided evidence that multiple independent clones derived from DCIS evolve into IBC, although the molecular mechanisms of progression from DCIS to IBC remain elusive 52 , 53 (Figure 1). Inhibition of DCIS progression to IBC is an important preventive therapeutic strategy against breast cancer.

FIGURE 1.

FIGURE 1

Open in a new tab

Ductal carcinoma in situ (DCIS) initiation and growth. The acquisition of oncogenic mutations in single luminal epithelial cells leads to DCIS. DCIS is an early stage lesion in which abnormal cancerous cells grow and remain within the mammary ducts. Cancer cells grow and become invasive, progressing to invasive ductal carcinoma (IBC) when they spread beyond the basement membrane and invade surrounding stromal tissue. Epithelial‐mesenchymal transition (EMT) in cancer cells, infiltration of cancer‐associated fibroblasts (CAFs) and immune cells in the tumor microenvironment, and inflammatory cytokines secreted from both cancer cells and the DCIS microenvironment are essential for the progression of DCIS to IBC.

Currently, available preventive treatment options include surgery and pharmacological therapies. Most patients with DCIS undergo breast‐conserving surgery or bilateral mastectomy with postoperative radiation or hormonal therapy as required. 54 As this series of surgical treatments is similar to the treatment for IBC, there is a risk of overtreatment for DCIS. DCIS lesions are frequently found in autopsy cases with causes of death other than breast cancer. This indicates that further treatment is not necessary for such low‐risk DCIS lesions. However, there are no accurate diagnostic methods for predicting DCIS progression to IBC.

Hormonal therapies recommended by international guidelines to reduce the risk of local recurrence or tumor development in contralateral breast tissues after surgery include selective estrogen receptor modulator (SERMs) tamoxifen 55 and raloxifene, 56 and the aromatase inhibitors exemestane and anastrozole. 57 , 58 These drugs have been reported to reduce the risk of hormone receptor‐positive breast cancer. Aromatase inhibitors have fewer side effects than SERMs and are considered better alternatives to first‐line SERMs with strong side effects. 59 Other drugs currently in clinical trials include metformin, a type 2 diabetes drug, 60 and retinoids. 61

Receptor activator of NF‐κB (RANK) and its ligand (RANKL) play important roles in the development of breast cancer in BRCA1 mutation carriers. 62 Compared to healthy individuals, RANK‐positive ductal epithelial progenitor cells are elevated in BRCA1 mutation carriers. These RANK‐positive progenitor cells are the cells of origin of breast cancer in BRCA1 mutation carriers. 63 DNA damage induced by BRCA1 deficiency increases RANK signaling, which activates NF‐κB, leading to tumorigenesis. The RANK monoclonal antibody denosumab, which inhibits RANK activity and is used as an osteoporosis drug, has been reported to suppress the development of mammary tumors in Brac1‐knockout mice. 64 Furthermore, breast cancer biopsy tissues from patients with BRCA1 mutations showed increased RANK expression, which is positively correlated with the risk of breast cancer development. The results of a clinical trial of denosumab showed that it is beneficial for reducing the risk of breast cancer development in BRCA1 mutation carriers.

4. ErbB2‐FRS2β‐NF‐κB AXIS‐CREATED CYTOKINE‐ENRICHED INFLAMMATORY PREMALIGNANT MICROENVIRONMENT IS ESSENTIAL FOR BREAST CANCER DEVELOPMENT

Statistical data on the reduction of breast cancer incidence and mortality using NSAIDS suggest that inflammatory changes are involved in breast cancer development. 65 , 66 However, the molecular mechanisms underlying inflammatory changes during the initiation of breast cancer remain elusive. Recently, we identified novel molecular mechanisms of inflammatory changes in the development of breast cancer. 67 We used mouse mammary tumor virus (MMTV)‐ErbB2 mice, in which overexpression of the receptor tyrosine kinase ErbB2 in mammary epithelial cells causes disease onset and stepwise progression from hyperplasia to DCIS and IBS. 68 This mouse model recapitulates the development of human breast cancer, particularly that of the ErbB2/HER2‐positive subtype.

We focused on FRS2β, an adaptor protein that does not possess enzymatic activity and binds to receptor tyrosine kinases (RTKs). FRS2β belongs to the FRS2 family of proteins, which consists of two proteins, FRS2α and FRS2β. Both proteins have similar structures and a myristylation signal, a phosphotyrosine binding (PTB) domain, and multiple tyrosine phosphorylation sites (Figure 2). 69 Using the myristylation signal, they bind to the plasma membrane or endosomal membrane. Upon activation of a limited number of RTKs (FGFR, neutrophin receptor, RET, and ALK), FRS2 proteins bind to RTKs via their PTB domain and become phosphorylated on tyrosine residues. Phosphorylated FRS2 proteins bind to Shp2 and Grb2 to activate the RAS/ERK and phosphatidylinositol 3‐kinase (PI3K) signaling pathways, respectively. FRS2α and FRS2β act in a redundant manner downstream of RTKs. FRS2β binds to epidermal growth factor receptor (EGFR) family members, including ErbB2; however, it is phosphorylated on either tyrosine or serine/threonine residues by activated EGFR or ErbB2. We previously reported that FRS2β negatively regulates the RAS/ERK signaling pathway downstream of the activated EGFR, suggesting that FRS2β exhibits a tumor‐suppressive role in lung cancer, contrary to the expected roles of FRS2α. 70 , 71 FRS2β is expressed mainly in the brain, with little expression in other tissues, whereas FRS2α shows ubiquitous expression. Mutant mice deficient in Frs2β (−/−) are healthy and fertile without gross abnormalities, whereas Frs2α (−/−) mice have embryonic lethality. Although these findings suggest that FRS2β has unique functions that differ from those of FRS2α, the role of FRS2β has long been enigmatic. We found that FRS2β was expressed in a few mammary epithelial cells, particularly luminal progenitor cells (Figure 3). This prompted us to investigate its role in mammary tumorigenesis.

FIGURE 2.

FIGURE 2

Open in a new tab

Schematic structure of FRS2β and downstream signaling pathways. FRS2β is an adaptor protein that interacts with activated receptor tyrosine kinase (RTK). FRS2β has a myristylation consensus sequence (M; MGXXXS/T), phosphotyrosine biding domain (PTB), ERK binding domain (ERK), and five tyrosine phosphorylation sites (Y). Among the five phosphorylation sites on FRS2β, three contain the consensus sequence for the SH2 domain of Grb2 (YXNX), while the other two phosphorylation sites bind to Shp2, the SH2‐containing tyrosine phosphatase. FRS2β activates the phosphatidyl inositol 3‐kinase (PI3K) and RAS/ERK pathways through the Grb2 and Shp2 binding domains, respectively.

FIGURE 3.

FIGURE 3

Open in a new tab

FRS2β plays critical roles in the creation of the cytokine‐enriched niche that is required for mammary tumorigenesis. FRS2β is expressed in a small subset of luminal cells and induces the secretion of various cytokines, including IGF1 and CXCL12. IGF1 stimulates cancer stem cells and cancer cells to promote stemness, cell proliferation, and resistance to apoptosis. CXCL12 affects cancer‐associated fibroblasts (CAFs) to induce their migration to the tumor microenvironments. After a long latency in association with the chronic inflammatory changes, a cytokine‐rich microenvironment is established that promotes the growth of cancer cells (left). In the absence of FRS2β, cytokine production is restricted to induction of tumor formation (right).

By crossing Frs2β (−/−) mice with MMTV‐ErbB2 mice, MMTV‐ErbB2/Frs2β (−/−) mice were produced. Tumor growth was remarkably suppressed in MMTV‐ErbB2/Frs2β (−/−) mice because cytokine‐enriched premalignant mammary tissues, which are found to be essential for disease onset, were not observed (Figure 3). We found that on early endosomes, FRS2β was colocalized not only with ErbB2 but also with NEMO (also known as IκB kinase [IKK]γ), which is a scaffolding protein included in the IKK complex for NF‐κB activation (Figure 4). The IKK complex includes two other catalytic subunits: IKKα and IKKβ. It phosphorylates NF‐κB‐bound IκBs, thereby targeting them for proteasomal degradation and liberating NF‐κB dimers composed of RelA (also known as p65) and p50 to enter the nucleus and mediate the transcription of target genes. This is a novel molecular mechanism for NF‐κB activation (Figure 2). Activated NF‐κB stimulates the transcription of a variety of cytokines; among them, insulin growth factor (IGF)1 and CXCL12 are at the top of the list (Figure 3). IGF1 stimulates self‐renewal and growth of cancer stem cells, while CXCL12 induces the migration of cancer‐associated fibroblasts (CAFs) as a chemoattractant. By treatment with neutralizing antibodies against IGF1 combined with inhibitors of CXCR4 and CXCF7, which are the receptors for CXCL12, tumorigenesis was greatly suppressed to levels similar to those in MMTV‐ErbB2/Frs2β (−/−) mice. Therefore, the ErbB2–FRS2β‐NF–κB axis creates a premalignant inflammatory microenvironment that is essential for breast cancer development.

FIGURE 4.

FIGURE 4

Open in a new tab

FRS2β binds to ErbB2, and they co‐localized on the early endosomes. Further, FRS2β co‐localizes with the IκB kinase (IKK) complex, including NEMO, IKKα and IKKβ, and TAK1, an activator for the IKK complex, on the early endosomes. Activated IKK phosphorylates IκB, leading to ubiquitylation and degradation of IκB in the complex with p50 and RelA. Then, p50 and RelA dimer is released from IκB binding, enters the nucleus, and acts as NFκB transcription factor. Therefore, the FRS2β–ErbB2 complex on early endosomes is considered to function as a signaling hub in subsequent NF‐κB pathways.

5. CONCLUSION

Further research is necessary to develop precision medicine for cancer prevention by targeting the mammary tissue before disease onset. In particular, it is important to establish breast cancer‐specific biomarkers that can predict the existence of malignant DCIS, which has strong potential for progression to IBS. Although inflammation is important for disease onset, we should consider that signaling pathways induced by inflammation are complex and diverse and that biomarkers using blood or urine may detect inflammatory reactions outside of the mammary tissue. Recently, a novel method for detecting circulating tumor DNA (ctDNA) in the blood using liquid biopsy has been developed. This technique may be applicable to patients with early stage breast cancer. 72

FRS2β may be used as a biomarker to evaluate the risk of breast cancer because it can be used to analyze the cytokine‐rich mammary microenvironment, which is the basis of carcinogenesis. FRS2β expression can be detected in biopsy specimens or surgically resected tissues using immunohistochemistry. Whether FRS2β contributes to not only HER2‐positive subtypes but also other subtypes, such as hormone receptor‐positive or triple‐negative subtypes, needs to be further analyzed. It is also important to analyze the premalignant mammary tissue microenvironment in more detail using newly developed technologies such as single‐cell RNA sequencing and spatial transcriptomics to clarify the changes in a variety of cell populations, including premalignant epithelial cells, immune cells, CAFs, and endothelial cells. 73

Effective cancer prevention will be possible through the development of a comprehensive breast cancer prediction model that combines new biomarkers, molecular genetics, mammography, and other clinical information. Artificial intelligence is a promising technology for increasing the accuracy of prediction models in the future.

FUNDING INFORMATION

This work was supported in part by JSPS KAKENHI grant numbers JP16H06279 (AdAMS), JP16H06277 (CoBiA), JP 18H02679, JP19K22557, JP20H05029, and JP21H02761 and a research grant from AMED Project for Cancer Research and Therapeutic Evolution (19193063 and 21446781) to N. Gotoh.

CONFLICT OF INTEREST STATEMENT

The authors have no potential conflicts to disclose.

DISCLOSURE

Noriko Gotoh is an associate editor at Cancer Science.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Reviewer Board. N/A.

Informed Consent. N/A.

Registry and the Registration No. of the study/trial. N/A.

Animal Studies.

Mice were handled according to the guidelines of the Institute for Experimental Animals, Kanazawa University. Animal experiments were approved by the committee for animal research of Kanazawa University (approved number: AP‐194036).

Takeuchi Y, Gotoh N. Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers. Cancer Sci. 2023;114:1792‐1799. doi: 10.1111/cas.15734

REFERENCES

  • 1. Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer. 2020;20:417‐436. [DOI] [PubMed] [Google Scholar]
  • 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7‐34. [DOI] [PubMed] [Google Scholar]
  • 3. Fitzmaurice C, Akinyemiju TF, Al Lami FH, et al. Global, regional, and National Cancer Incidence, mortality, years of life lost, years lived with disability, and disability‐adjusted life‐years for 29 cancer groups, 1990 to 2016 a systematic analysis for the global burden of disease study. JAMA Oncol. 2018;4:1553‐1568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Miki Y, Swensen J, Shattuckeidens D, et al. A strong candidate for the breast and ovarian‐cancer susceptibility gene Brca1. Science. 1994;266:66‐71. [DOI] [PubMed] [Google Scholar]
  • 5. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast‐cancer susceptibility gene Brca2. Nature. 1995;378:789‐792. [DOI] [PubMed] [Google Scholar]
  • 6. Beral V, Bull D, Doll R, et al. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet. 2002;360:187‐195. [DOI] [PubMed] [Google Scholar]
  • 7. Beral V, Bull D, Pirie K, et al. Menarche, menopause, and breast cancer risk: individual participant meta‐analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13:1141‐1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Collaborative Group on Hormonal Factors in Breast Cancer . Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta‐analysis of the worldwide epidemiological evidence. Lancet. 2019;394:1159‐1168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Tarone RE. Age at first and last births and risk of breast‐cancer. Epidemiology. 1995;6:465. [PubMed] [Google Scholar]
  • 10. Suzuki R, Orsini N, Saji S, Key TJ, Wolk A. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status‐a meta‐analysis. Int J Cancer. 2009;124:698‐712. [DOI] [PubMed] [Google Scholar]
  • 11. Zahid H, Simpson ER, Brown KA. Inflammation, dysregulated metabolism and aromatase in obesity and breast cancer. Curr Opin Pharmacol. 2016;31:90‐96. [DOI] [PubMed] [Google Scholar]
  • 12. Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306:1884‐1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Kehm RD, Genkinger JM, MacInnis RJ, et al. Recreational physical activity is associated with reduced breast cancer risk in adult women at high risk for breast cancer: a cohort study of women selected for familial and genetic risk. Cancer Res. 2020;80:116‐125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Xuan CY, Shamonki JM, Chung A, et al. Microbial dysbiosis is associated with human breast cancer. PLoS One. 2014;9:e83744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type‐specific intracellular bacteria. Science. 2020;368:973‐980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Karin M, Clevers H. Reparative inflammation takes charge of tissue regeneration. Nature. 2016;529:307‐315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883‐899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Taniguchi K, Karin M. NF‐kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309‐324. [DOI] [PubMed] [Google Scholar]
  • 19. Karin M, Greten FR. NF‐kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749‐759. [DOI] [PubMed] [Google Scholar]
  • 20. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer‐related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073‐1081. [DOI] [PubMed] [Google Scholar]
  • 21. Shimizu T, Marusawa H, Endo Y, Chiba T. Inflammation‐mediated genomic instability: roles of activation‐induced cytidine deaminase in carcinogenesis. Cancer Sci. 2012;103:1201‐1206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Shigdar S, Li Y, Bhattacharya S, et al. Inflammation and cancer stem cells. Cancer Lett. 2014;345:271‐278. [DOI] [PubMed] [Google Scholar]
  • 23. Pires BRB, Mencalha AL, Ferreira GM, et al. NF‐kappaB is involved in the regulation of EMT genes in breast cancer cells. PLoS One. 2017;12:e0169622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Godwin P, Baird AM, Heavey S, Barr MP, O'Byrne KJ, Gately K. Targeting nuclear factor‐kappa B to overcome resistance to chemotherapy. Front Oncol. 2013;3:120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin CC, Flavell RA. Inflammation‐induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759‐771. [DOI] [PubMed] [Google Scholar]
  • 26. Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer. 2016;16:173‐186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Rothwell PM, Wilson M, Elwin CE, et al. Long‐term effect of aspirin on colorectal cancer incidence and mortality: 20‐year follow‐up of five randomised trials. Lancet. 2010;376:1741‐1750. [DOI] [PubMed] [Google Scholar]
  • 28. Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C. Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol. 2012;23:1403‐1415. [DOI] [PubMed] [Google Scholar]
  • 29. Cuzick J, Thorat MA, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol. 2015;26:47‐57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX‐2. N Engl J Med. 2007;356:2131‐2142. [DOI] [PubMed] [Google Scholar]
  • 31. Ranger GS. Current concepts in colorectal cancer prevention with cyclooxygenase inhibitors. Anticancer Res. 2014;34:6277‐6282. [PubMed] [Google Scholar]
  • 32. Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase‐2. Nat Rev Cancer. 2001;1:11‐21. [DOI] [PubMed] [Google Scholar]
  • 33. MacDonald BT, Tamai K, He X. Wnt/beta‐catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9‐26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Atretkhany KSN, Drutskaya MS, Nedospasov SA, Grivennikov SI, Kuprash DV. Chemokines, cytokines and exosomes help tumors to shape inflammatory microenvironment. Pharmacol Ther. 2016;168:98‐112. [DOI] [PubMed] [Google Scholar]
  • 35. Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Investig. 2015;125:3347‐3355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. DiDonato JA, Mercurio F, Karin M. NF‐kappa B and the link between inflammation and cancer. Immunol Rev. 2012;246:379‐400. [DOI] [PubMed] [Google Scholar]
  • 37. Ben‐Neriah Y, Karin M. Inflammation meets cancer, with NF‐kappa B as the matchmaker. Nat Immunol. 2011;12:715‐723. [DOI] [PubMed] [Google Scholar]
  • 38. Hopewell EL, Zhao WP, Fulp WJ, et al. Lung tumor NF‐kappa B signaling promotes T cell‐mediated immune surveillance. J Clin Investig. 2013;123:2509‐2522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787‐795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541‐566. [DOI] [PubMed] [Google Scholar]
  • 41. Evaristo C, Spranger S, Barnes SE, et al. Cutting edge: engineering active IKK beta in T cells drives tumor rejection. J Immunol. 2016;196:2933‐2938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Grinberg‐Bleyer Y, Oh H, Desrichard A, et al. NF‐kappa B c‐Rel is crucial for the regulatory T cell immune checkpoint in cancer. Cell. 2017;170:1096‐1108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Karyampudi L, Lamichhane P, Krempski J, et al. PD‐1 blunts the function of ovarian tumor‐infiltrating dendritic cells by inactivating NF‐kappa B. Cancer Res. 2016;76:239‐250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Tu SP, Bhagat G, Cui GL, et al. Overexpression of Interleukin‐1 beta induces gastric inflammation and cancer and mobilizes myeloid‐derived suppressor cells in mice. Cancer Cell. 2008;14:408‐419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9:503‐510. [DOI] [PubMed] [Google Scholar]
  • 46. Casasent AK, Almekinders MM, Mulder C, et al. Learning to distinguish progressive and non‐progressive ductal carcinoma in situ. Nat Rev Cancer. 2022;22:663‐678. [DOI] [PubMed] [Google Scholar]
  • 47. Berman HK, Gauthier ML, Tlsty TD. Premalignant breast neoplasia: a paradigm of interlesional and intralesional molecular heterogeneity and its biological and clinical ramifications. Cancer Prev Res. 2010;3:579‐587. [DOI] [PubMed] [Google Scholar]
  • 48. Wilkinson L, Thomas V, Sharma N. Microcalcification on mammography: approaches to interpretation and biopsy. Br J Radiol. 2017;90:20160594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Shaaban AM, Hilton B, Clements K, et al. Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane project. Br J Cancer. 2021;124:1009‐1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Groen EJ, Hudecek J, Mulder L, et al. Prognostic value of histopathological DCIS features in a large‐scale international interrater reliability study. Breast Cancer Res Treat. 2020;183:759‐770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Visser LL, Groen EJ, van Leeuwen FE, Lips EH, Schmidt MK, Wesseling J. Predictors of an invasive breast cancer recurrence after DCIS: a systematic review and meta‐analyses. Cancer Epidemiol Biomarkers Prev. 2019;28:835‐845. [DOI] [PubMed] [Google Scholar]
  • 52. Casasent AK, Edgerton M, Navin NE. Genome evolution in ductal carcinoma in situ: invasion of the clones. J Pathol. 2017;241:208‐218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Hong Y, Limback D, Elsarraj HS, et al. Mouse‐INtraDuctal (MIND): an in vivo model for studying the underlying mechanisms of DCIS malignancy. J Pathol. 2022;256:186‐201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Li X, You R, Wang XW, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: a meta‐analysis and systematic review. Clin Cancer Res. 2016;22:3971‐3981. [DOI] [PubMed] [Google Scholar]
  • 55. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long‐term follow‐up of the IBIS‐I breast cancer prevention trial. Lancet Oncol. 2015;16:67‐75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the national surgical adjuvant breast and bowel project study of tamoxifen and raloxifene (STAR) P‐2 trial: preventing breast cancer. Cancer Prev Res. 2010;3:696‐706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Dowsett M, Cuzick J, Ingle J, et al. Meta‐analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010;28:509‐518. [DOI] [PubMed] [Google Scholar]
  • 58. Cuzick J. Aromatase inhibitors for breast cancer prevention. J Clin Oncol. 2005;23:1636‐1643. [DOI] [PubMed] [Google Scholar]
  • 59. Cuzick J, Sestak I, Forbes JF, et al. Use of anastrozole for breast cancer prevention (IBIS‐II): long‐term results of a randomised controlled trial. Lancet. 2020;395:117‐122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Rojas LBA, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Jin Y, Teh SS, Lau HLN, Xiao JB, Mah SH. Retinoids as anti‐cancer agents and their mechanisms of action. Am J Cancer Res. 2022;12:938‐960. [PMC free article] [PubMed] [Google Scholar]
  • 62. Rao S, Cronin SJF, Sigl V, Penninger JM. RANKL and RANK: from mammalian physiology to cancer treatment. Trends Cell Biol. 2018;28:213‐223. [DOI] [PubMed] [Google Scholar]
  • 63. Nolan E, Vaillant F, Branstetter D, et al. RANK ligand as a potential target for breast cancer prevention in BRCA1‐mutation carriers. Nat Med. 2016;22:933‐939. [DOI] [PubMed] [Google Scholar]
  • 64. Nolan E, Lindeman GJ, Visvader JE. Out‐RANKing BRCA1 in mutation carriers. Cancer Res. 2017;77:595‐600. [DOI] [PubMed] [Google Scholar]
  • 65. Lu LM, Shi LY, Zeng JC, Wen ZH. Aspirin as a potential modality for the chemoprevention of breast cancer: a dose‐response meta‐analysis of cohort studies from 857,831 participants. Oncotarget. 2017;8:40389‐40401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. de Pedro M, Baeza S, Escudero MT, et al. Effect of COX‐2 inhibitors and other non‐steroidal inflammatory drugs on breast cancer risk: a meta‐analysis. Breast Cancer Res Treat. 2015;149:525‐536. [DOI] [PubMed] [Google Scholar]
  • 67. Takeuchi Y, Kimura N, Murayama T, et al. The membrane‐linked adaptor FRS2 beta fashions a cytokine‐rich inflammatory microenvironment that promotes breast cancer carcinogenesis. Proc Natl Acad Sci USA. 2021;118:e2103658118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA. 1992;89:10578‐10582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Gotoh N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 2008;99:1319‐1325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Manchado E, Weissmueller S, Morris JP, et al. A combinatorial strategy for treating KRAS‐mutant lung cancer. Nature. 2016;534:647‐651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Iejima D, Minegishi Y, Takenaka K, et al. FRS2beta, a potential prognostic gene for non‐small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding. Oncogene. 2010;29:3087‐3099. [DOI] [PubMed] [Google Scholar]
  • 72. Ignatiadis M, Sledge GW, Jeffrey SS. Liquid biopsy enters the clinic ‐ implementation issues and future challenges. Nat Rev Clin Oncol. 2021;18:297‐312. [DOI] [PubMed] [Google Scholar]
  • 73. Longo SK, Guo MG, Ji AL, Khavari PA. Integrating single‐cell and spatial transcriptomics to elucidate intercellular tissue dynamics. Nat Rev Genet. 2021;22:627‐644. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES